Amyloidogenesis. One serum amyloid A isotype is selectively removed from the circulation.

The deposits of fibrils found in amyloidosis of the A type are derived from only one of the three serum amyloid A (SAA) gene products, namely SAA2. In order to explore the mechanism of SAA isotype-specific amyloid protein AA deposition, the molecular kinetics of the serum amyloid proteins were examined in CBA mice during casein induction of amyloidosis. The presence of SAA mRNA in spleen was searched for; hepatic SAA1 and SAA2 mRNA levels, rates of specific protein synthesis and secretion by hepatocytes, and serum levels were measured during a 20-d period of amyloid induction. We observed the following: small amounts of amyloid substance appeared in the spleen by day 5 and increased steadily over the ensuing 15 d to occupy nearly 30% of splenic volume by day 20. No SAA mRNA was detected in spleen at any time during induction of amyloid formation. Total serum SAA levels peaked 1 d after we began casein treatment, and thereafter declined. This decline was accounted for entirely by a dramatic fall in SAA2, while SAA1 levels remained nearly constant throughout. The ratios of hepatic SAA2:SAA1 mRNA, as determined by in vitro translation, remained constant during the 20-d period, as did amounts of SAA1 and SAA2 synthesized and secreted by freshly isolated hepatocytes. These data indicate that the deposition of amyloid A protein derived from SAA2 is not due to local SAA production in spleen, nor excessive SAA2 production compared with SAA1, but involves the selective and accelerated removal of SAA2 from the circulating pool of both SAA1 and SAA2.

Murine tissue amyloid protein AA. NH2-terminal sequence identity with only one of two serum amyloid protein (ApoSAA) gene products.

Amyloid protein AA is the presumptive fragment of an acute phase serum apolipoprotein, apoSAA. Two major murine apoSAA isotypes (apoSAA1 and apoSAA2) have been identified. The NH2-terminal amino acid sequences of purified murine apoSAA1 and apoSAA2 have been examined and compared with that of murine amyloid protein AA. Our results indicate that apoSAA1 and apoSAA2 are separate gene products and that amyloid protein AA has NH2-terminal amino acid sequence identity with only one of these isotypes, namely apoSAA2.

Plasma clearance kinetics of the amyloid-related high density lipoprotein apoprotein, serum amyloid protein (apoSAA), in the mouse. Evidence for rapid apoSAA clearance.

The plasma clearance kinetics of the amyloid-related high density lipoprotein (HDL) apoprotein serum amyloid protein (apoSAA) was examined in BALB/c mice by two different methods, using labeled 125I-apoSAA-rich HDL and unlabeled plasma apoSAA (clearance monitored by radioimmunoassay). The plasma half-life of apoSAA, estimated by both methods, was on the order of 75-80 min, as compared with a value of approximately 11 h for mouse apoA-I. In trace-labeling studies, the rapid plasma clearance of both major 125I-labeled apoSAA isotypes was observed; this metabolic behavior was unique to these polypeptides among HDL apoproteins. The property of rapid plasma clearance was lost upon purification and reconstitution of 125I-apoSAA with HDL, indicating that this property is labile to denaturing conditions. Studies aimed at determining the metabolic fate of 125I-apoSAA gave no evidence for either the selective excretion of 125I-apoSAA or clearance to unique tissue sites as compared with other 125I-HDL apoproteins.

Changes in cell cycle-associated gene expression in a model of impaired liver regeneration.

Following partial hepatectomy (PH) there is compensatory regeneration of the remnant liver which eventually restores hepatic mass and function. The response to PH was studied in normal BALB/c and athymic nude mice, a model of impaired liver regeneration. Following PH, nude mice demonstrated diminished peak hepatic [3H]thymidine uptake and delayed liver mass restoration through 60 h post-PH. However, between 72-120 h there was no significant difference in mass restoration between the groups. The expression of genes associated with different stages of the cell cycle was evaluated in both models. In nude mice, there was an increase in peak expression of c-jun transcripts, while c-myc transcript expression was moderately attenuated. Thymidine kinase (TK) and cyclin-dependent kinase 1 (CDK1) mRNA expression was also diminished in athymic nude mice. The results suggest that while the defect in the regenerative response of the nude mouse after PH affects events in several phases of the cell cycle, mass restoration of the liver is only delayed and not attenuated.

Efficacy of a 1-week regimen of ranitidine bismuth citrate in combination with metronidazole and clarithromycin for Helicobacter pylori eradication.

BACKGROUND: In order to improve the efficacy and simplicity of the FDA-approved regimen of ranitidine bismuth citrate (RBC) and clarithromycin dual therapy, we added an inexpensive antibiotic (metronidazole), changed the dosage scheme to twice daily dosing, and decreased the duration of therapy to 1 week. METHODS: This was an open label study in which subjects with previously untreated Helicobacter pylori infection documented by serology or endoscopy and confirmed by the 13C-urea breath test received a 1-week course of RBC 400 mg b.d., metronidazole 500 mg b.d. and clarithromycin 500 mg b.d. A repeat breath test was performed 4-6 weeks after completing therapy. RESULTS: Forty-seven out of 50 subjects completed the protocol. Intention-to-treat and per protocol cure rates were 86% and 91%, respectively. The regimen was well tolerated. Study drugs were stopped in two patients due to side-effects. The most common side-effect was self-limited diarrhoea. CONCLUSION: Twice daily RBC-based triple therapy with metronidazole and clarithromycin for 1 week is well tolerated and effective in eradicating H. pylori infection.

SAA, an apoprotein of HDL: its structure and function.

The putative precursor of amyloid protein AA appears in serum as an apoprotein (apoSAA) of heavier HDL fractions of lipoproteins found in humans and mice. ApoSAA is found by precipitation with specific anti-AA antibodies to be on a particle that also carries apoA-I and some C-apoproteins. In endotoxin-treated mice a lipoprotein fraction with about 2 moles of apoSAA to 1 mole of apoA-I can be isolated, an apoSAA-carrying subset of HDL being thus suggested. In mice, rapid clearance from plasma of native apoSAA compared to apoA-I suggests a special function for apoSAA. The C-terminal amino acid portion of apoSAA may play a role in this function.

Prognostic significance of groin lymph node metastases in squamous carcinoma of the vulva.

A retrospective review of the clinical and histologic findings in 48 cases of stages I, II, and III (excluding T3) squamous carcinoma of the vulva with positive groin nodes reveals the prognostic significance of the size and number of the nodal metastases. Other factors such as the morphology of the lymph nodes and the histologic features of the primary neoplasm are not nearly as significant. Patients with only one or two small nodal metastases have an excellent outlook for survival providing that adequate margins can be obtained around the primary tumor and that thorough groin node dissections can be performed. These patients do not appear to need adjuvant radiation or pelvic node dissection. A further finding is that patients with unilateral labial carcinomas do not have metastases to the opposite groin in the absence of ipsilateral groin metastases, although six of 21 patients had metastases to both groins.

Microinvasive squamous carcinoma of the vulva: search for a definition.

All cases of stage I squamous cell carcinoma of the vulva from the University of Michigan Tumor Registry from 1935 to 1981 were reviewed. Seventeen of 90 (19%) patients had nodal metastases. All had a depth of invasion of more than 2 mm and all exhibited histologic confluence. The risk of nodal metastases varied with depth of invasion, size of lesion, and histologic grade, although the association with grade was not statistically significant. The size of the lesion influenced the incidence of nodal metastases only in that it was associated with the depth of invasion. Lymphovascular invasion was present in only four patients, but three of them had nodal metastases, including one patient with only 3 mm depth of invasion.

Integrating biologic and psychologic treatment: the need for a unitary model.

Psychiatric illness tends to be conceptualized as either a biologic or psychologic process, a dichotomy that is inevitably reflected in treatment. A unitary model encourages the psychotherapist to incorporate biologic modalities as a meaningful interaction within the therapy. The biologic therapist, in turn, can be more effective when aware that even severe mental illness is also a psychologic process. Causality cannot be inferred from severity of illness nor should it be used to rationalize a two-track approach to treatment. Biologic treatment should never be considered a treatment of last resort.

Enhanced mutagenesis during post-treatment incubation of Escherichia coli treated with cis-diamminedichloroplatinum(II).

Wild-type Escherichia coli were treated with cis-dichlorodiammineplatinum(II) (DDP) and then kept in a non-dividing state for 4 h. This post-treatment incubation did not increase survival, excision of platinum-DNA lesions was not observed, and post-treatment exposure to thiourea had no effect on the toxicity of DDP. In contrast, the mutation frequency increased by a factor of 3 and reached a plateau after 3 h incubation at 37 degrees C. The quantity of DDP on the bacterial DNA remained constant during this time. Post-treatment exposure to thiourea (which is reported to react with monofunctional platinum-DNA adducts) inhibited but did not reverse the increased mutagenicity. These results may reflect the evolution of monofunctional platinum-DNA lesions into bifunctional mutagenic adducts during post-treatment incubation of bacteria which have been exposed to DDP.

Tolerance during long-term administration of intrathecal morphine.

We studied the time course of development of tolerance in four terminally ill cancer patients who were treated for intractable pain by intrathecal morphine administered by an implanted catheter and pump. The duration of treatment varied from 1.8 to 10.5 months. Our study shows that with disease progression, there was a constant patient-specific time rate of increase in the morphine dose requirements. Hence, for any given patient, the slope of the dose v time curve is effectively a constant over long periods. We also found that patients tolerate very high doses of intrathecal morphine without serious side effects.

Dysgerminoma: a study of 13 cases from the Connecticut Tumor Registry.

Thirteen cases of patients with dysgerminoma of the ovary, accrued from the Connecticut Tumor Registry from 1974-84, were reviewed. Seven of the 13 patients were stage I at the time of initial surgery. Two of these patients had a diagnosis of dysgerminoma arising within a gonadoblastoma. Five of the seven patients were treated with some form of adnexal surgery; one patient received adjuvant combination chemotherapy consisting of vincristine, dactinomycin, and cyclophosphamide (VAC) and another received radiation therapy. Two of the seven patients were treated with total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH/BSO) plus radiation therapy. One patient, whose tumor recurred after initial therapy with unilateral oophorectomy, was successfully treated with radiation therapy. Six patients had advanced disease at the time of initial surgery. One patient with stage II disease and three patients with stage III disease were treated with TAH/BSO plus radiation therapy. One patient with stage III disease was treated with unilateral adnexectomy plus combination chemotherapy consisting of vinblastine, bleomycin, dactinomycin, cyclophosphamide, and cisplatin (VAB-VI). One patient with stage IV disease was treated with decompressive laminectomy with tumor resection, removal of left pelvic mass, radiation therapy and adjuvant combination chemotherapy (VAC). In our series, no patient died from dysgerminoma (one patient died of an apparently unrelated cause). The role of radiation therapy in the treatment of advanced and recurrent dysgerminoma has been demonstrated. However, the use of combination chemotherapy has been playing an increasingly important role in patients treated with conservative surgery in which preservation of fertility is a concern.

Sexual therapy for patients without partners.

Most available therapies for sexual dysfunction require a cooperative partner. This article describes a combined behavioral psychodynamic treatment program for sexual problems in people without partners. The method allows for flexibility in treating patients with widely varying personalities and levels of psychopathology.

Cetuximab potentiates oxaliplatin cytotoxic effect through a defect in NER and DNA replication initiation.

Preclinical studies have demonstrated that the chemotherapeutic action of oxaliplatin, a third generation platinum derivative, is improved when combined with cetuximab, a monoclonal antibody inhibitor of epidermal growth factor receptors. To explore the mechanism of this synergistic benefit, we used HCT-8 and HCT-116, two human colon cancer cell lines, respectively, responsive and non-responsive to the oxaliplatin/cetuximab combination. We examined the effect of drug exposure on glutathione-S-transferase-mediated oxaliplatin detoxification, DNA-platinum adducts formation, cell cycle distribution, apoptosis, and the expression of multiple targets involved in DNA replication, recombination, and repair. The major changes we found in HCT-8 were a stimulation of oxaliplatin-DNA adduct formation associated with reduced expression of the key enzyme (excision repair cross complementation group1: ERCC1) in the key repair process of oxaliplatin-DNA platinum adduct, the nucleotide excision repair (NER), both at the mRNA and protein levels. We also observed a reduced expression of factors involved in DNA replication initiation, which correlates with an enrichment of cells in the G1 phase of the cell cycle as well as an acceleration of apoptosis. None of these changes occurred in the non-responsive HCT-116 cell that we used as a negative control. These findings support the fact that cetuximab potentiates the oxaliplatin-mediated cytotoxic effect as the result of inhibition of NER and also DNA replication initiation.

Pollution prevention as a market-enhancing strategy: a storehouse of economical and environmental opportunities.

EPA's (Environmental Protection Agency) Green Lights Program for energy-efficient lighting illustrates the economic benefits and the market-transforming value of a pollution prevention philosophy. Using technologies available today, and assuming current prices, this program is expected to reduce air pollution 5%, while saving the nation's businesses up to 20 billion in electric bills every year. However, these pollution prevention and savings estimates may be low. As Green Lights transforms the market for lighting services by creating a higher demand for better technologies at lower costs, the program will likely achieve even larger pollution reductions and electricity savings.

Pharmacological therapy of Helicobacter pylori infection.

Helicobacter pylori has been associated with several diseases including peptic ulcer disease and gastric cancer. Eradication of H pylori not only results in ulcer healing, but reduces recurrences essentially curing peptic ulcer disease. Eradicating H pylori can be difficult. There are several reasons for antimicrobial failure, and the resistance rates for several antibiotics are increasing. The most common drugs used to treat this infection include amoxicillin, clarithromycin, tetracycline, bismuth, and omeprazole and lansoprazole. Dual therapy using a proton pump inhibitor and a single antibiotic gives a suboptimal eradication rate. Triple therapy using at least two antibiotics and either bismuth or a proton pump inhibitor gives satisfactory eradication rates of 90%. However, these regimens are complicated and have significant side effects and compliance problems. The ideal regimen has yet to be developed. In the future, we will prevent infection with immunization. Several vaccines are being developed.

The political correctness of a physician hospital organization may precipitate its demise in a community hospital.

Health maintenance organizations are placing an increased pressure on physicians and hospitals to assume the risk of providing health care services under capitated agreements. They believe that if the providers' profits are based upon their cost-efficient provision of medical services, they will control their use of medical resources and reduce health care spending. Managing the risks of a capitated contract necessitates the integration of the hospital's and the physician's incentives. However, is the most appropriate legal structure that will enable physicians and hospitals to form risk-sharing contracts with managed care entities and manage these contracts profitably a physician-hospital organization? It is estimated that over 50 percent of the physician-hospital organizations that are created each year fail within the first two years of their operation because of political and financial reasons. A multispecialty group composed of select physicians, who are willing to integrate their practices and who have a low length of stay in the hospital, may be in a better position to manage the risks imposed by capitated contracts.

Central nervous system lesions and advanced ovarian cancer.

Over the past 5 years we have seen seven cases of central nervous system tumors in patients with advanced or recurrent ovarian carcinoma. These have ranged in location from the conus medullaris to the brain and have varied in time of occurrence from the time of cancer diagnosis to 63 months following surgery. A diagnosis of metastatic ovarian carcinoma was established in six of the cases, while one patient had a second primary malignancy. All cases had prodromal and localizing neurologic symptoms which led to the suspicion of central nervous system involvement. The critical diagnostic studies were myelography and computed tomography of the brain and spine. We have reviewed our approach to diagnosis and therapy.